Sex Differences in the Exocrine Pancreas and Associated Diseases

Abstract

Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated with pancreatic surgery in women. Although diagnostic criteria for pancreatitis are the same in men and women, major sex differences in etiology are reported. Alcohol and tobacco predominate in men, whereas idiopathic and obstructive etiologies predominate in women. Circulating levels of estrogens, progesterone, and androgens contribute significantly to overall health outcomes; premenopausal women have lower prevalence of cardiovascular and pancreatic diseases suggesting protective effects of estrogens, whereas androgens promote growth of normal and cancerous cells. Sex chromosomes and gonadal and nongonadal hormones together determine an individual's sex, which is distinct from gender or gender identity. Human pancreatic disease etiology, outcomes, and sex-specific mechanisms are largely unknown. In rodents of both sexes, glucocorticoids and estrogens from the adrenal glands influence pancreatic secretion and acinar cell zymogen granule numbers. Lack of corticotropin-releasing factor receptor 2 function, a G protein-coupled receptor whose expression is regulated by both estrogens and glucocorticoids, causes sex-specific changes in pancreatic histopathology, zymogen granule numbers, and endoplasmic reticulum ultrastructure changes in acute pancreatitis model. Here, we review existing literature on sex differences in the normal exocrine pancreas and mechanisms that operate at homeostasis and diseased states in both sexes. Finally, we review pregnancy-related pancreatic diseases and discuss the effects of sex differences on proposed treatments in pancreatic disease.

Keywords: Adrenal Steroids; Corticotropin-Releasing Factor Receptor 2; Estradiol; Exocrine Pancreas; Sex Differences; Sex Hormones.

Figure 1

Sex-specific differences in pancreatic function, morphology, and anatomy. (A) The gonads, adrenal gland, brain, and the placenta are primary steroidogenic tissues in humans capable of synthesizing all steroid hormones from cholesterol. Peptide hormones such as gonadotropin-releasing hormone (GnRH), FSH, and LH also modulate release of sex steroid hormones from the gonads, whereas CRF/ACTH actions result in synthesis and release of glucocorticoids from the adrenal glands. Adipose tissues are also known to perform steroidogenesis and synthesize estrogens; pancreas and pancreatic fat may also be capable of synthesizing and releasing estrogens, androgens, and progesterone. These steroid hormones bind to their cognate receptors and translocate to the nucleus, where the hormone-bound receptor complex binds to their respective hormone-response elements on the DNA to influence transcription of several target genes. The endocrine, paracrine, and autocrine actions of these hormones activate or repress several autosomal genes, such as CRH, CRHR2, ATG5, and other unknown ones (represented with etc.), which then modulate sex-specific signaling or pathways in the pancreas at baseline and in diseased state. (B) Schematic representation of human pancreatic size and volume with women on an average displaying less volume and a smaller pancreatic duct than men. (C) Radiograph imaging of the human abdomen showing pancreatic head, body, and tail in relation to other organs. (D) Radiocontrast imaging depicting cannulation of the pancreatic duct during an endoscopic retrograde cholangiopancreatography procedure. These anatomical differences in the pancreas may explain risk factors for different pancreatic diseases, including an increased risk of postendoscopic retrograde cholangiopancreatography pancreatitis in women compared with men. FSH, follicle-stimulating hormone; LH, luteinizing hormone; R, right side of patient.

Figure 2

Factors that influence sex differences in disease outcomes. Sex differences in pancreatic disease maybe caused by many factors that include genetic differences due to differences in X and Y sex chromosomes, modulation of autosomes by sex hormones, imprinted genes, epigenetic changes, genetic mutations or single nucleotide polymorphisms, environmental differences, gender differences, and differential regulation of the endocrine release of the hormones.